L-cystine stones account for less than 2% of adult kidney stones and affect more than 100,000 U.S. patients. L-cystine stones, which are larger and are more likely to cause chronic kidney disease than calcium oxalate monohydrate (COM) stones, form as a consequence of excessive levels of L-cystine in the urine due to defective reabsorption of filtered cystine [1]. This autosomal recessive disorder is caused by mutations in one of two genes coding for components of proximal renal tubule amino acid transporters. Affected genes are either SLC3A1 on chromosome 2 leading to type A cystinuria, or SLC7A9 on chromosome 19 leading to type B [2]. The low solubility of L-cystine [3] induces rapid crystallization, which is followed by aggregation to generate stones (FIG. 1A) with sizes that can achieve centimeter dimensions.
Current treatments include high fluid intake [4], increasing urine pH through ingestion of alkalinizing potassium or sodium salts [4, 5], or the administration of L-cystine binding thiol drugs (CBTDs), such as D-penicillamine (HS—C(CH3)2—CH(NH2)—COOH) and α-mercaptopropionylglycine (α-MPG or tiopronin: HS—CHCH3—CO—NH—CH2—COOH), which undergo a thiol-disulfide exchange with L-cystine to generate more soluble products [1]. These treatments suppress, but often do not completely prevent, stone formation. Thiol drugs have an unpleasant odor and can cause adverse side-effects, such as nausea, fever, fatigue, and skin allergies [5]. CBTDs are accompanied by high fluid intake to achieve a cystine excretion rate of 2.9 mM/day (i.e. urine volumes of 3 L/day) [4] and thiol excretion rates of 0.5-6 mM/day. A shortcoming of thiol drugs, however, is their inadequacy to reduce and solubilize large enough quantities of L-cystine in the urine based on acceptable dosages (up to 2000 mg/day), which are limited due to hypersensitivity and toxicity concerns.
Therefore, there is a need for an improved method to prevent, inhibit or slow L-cystine crystal production, and it is toward the fulfillment of that need that the present invention is directed.